Prolyl hydroxylase domain-containing protein (phd) inhibitors and uses thereof

ABSTRACT

Described herein are PHD inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of inflammatory bowel disease.

This patent application is a continuation of International ApplicationNo. PCT/CN2022/128293, filed Oct. 28, 2022, which claims the benefit ofInternational Application No. PCT/CN2021/127023, filed Oct. 28, 2021 andInternational Application No. PCT/CN2022/112270, filed Aug. 12, 2022;which are incorporated herein by reference in their entirety.

BACKGROUND

Hypoxia-inducible factor (HIF) mediates gene expression in response tochanges in cellular oxygen concentration. HIF is a heterodimer having anoxygen-regulated subunit (HIF-α) and a constitutively expressed subunit(HIF-β). HIF prolyl hydroxylase, which is also known as prolylhydroxylase domain-containing protein (PHD), exists as three isoforms inhumans (PHD1, PHD2, and PHD3). PHDs act as oxygen sensors modulating thehypoxia-inducible factor (“HIF”) degradation pathway. Briefly, PHDs areresponsible for hydroxylation of HIFα, a subunit of HIF, which initiatesthe pathway that eventually results in the degradation of HIFα by theproteasome. There are three subtypes of PHDs, including PHD1, PHD2 andPHD3. Inhibition of PHDs has been indicated as a promising therapy forthe HIFα related disease, such as inflammatory bowel disease (IBD).

Inhibitors of PHDs coordinate erythropoiesis by inducing both renal andhepatic erythropoietin (“EPO”) synthesis, which stimulates theproduction of red blood cells in the bone marrow, and by regulating themetabolism of iron, an indispensable component of functional red bloodcells. Inhibitors of PHDs could also suppress the production of hepatichepcidin, which has negative effects on iron mobilization. It is alsospeculated that inhibitors of PHDs might upregulate the expressionseveral iron metabolism gene, such as DMT1 and DCYTB. Because of thecentral role HIF prolyl hydrolase plays in cellular oxygen sensing,inhibitors of PHD may be useful in treating cardiovascular disorders,metabolic disorders, hematological disorders, pulmonary disorders,kidney disorders, liver disorders, wound healing disorders, and cancer,among others.

SUMMARY

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

-   wherein:-   R¹ monocyclic heterocycloalkyl optionally and independently    substituted with one or more R^(1a);-   each R^(1a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(1a) on the same atom are taken together to form an oxo;-   X is N or CR²;-   R² is hydrogen, fluoro, chloro, bromo, —CN, —NO₂, —OH, —OR^(a),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   R³ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁴ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   Y is —O—, —S—, or —NR⁶—;-   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   L is —(CR⁷R⁸)_(p);-   each R⁷ and R⁸ are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   or R⁷ and R⁸ on the same carbon are taken together to form a    cycloalkyl or heterocycloalkyl; each optionally substituted with one    or more R^(7a);-   each R^(7a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   p is 0-4;-   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R⁹ is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    optionally and independently substituted with one or more R^(9a);-   or two R⁹ on the same atom are taken together to form an oxo;-   each R^(9a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(9a) on the same atom are taken together to form an oxo;-   n is 0-4;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    R;-   each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    R;-   each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more R;-   or R^(c) and R^(d) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more R; and-   each R is independently halogen, —CN, —OH,—OC₁-C₆alkyl,    —S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂,    —S(═O)₂NHC₁-C₆alkyl, —S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl,    —N(C₁- C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —C(═O)OH,    —C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂,    —C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or-   two R on the same atom are taken together to form an oxo.

Also disclosed herein is a pharmaceutical composition comprising atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, anda pharmaceutically acceptable excipient.

Also disclosed herein is a method of treating a disease or disorder in asubject, the method comprising administering to the subject a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, or a pharmaceutical composition disclosed herein,wherein the disease or disorder is inflammatory bowel disease (IBD Insome embodiments of a method disclosed herein, the disease or disorderis ulcerative colitis (“UC”) or Crohn's disease (“CD”).

Also disclosed herein is a method of stabilizing hypoxia induciblefactor (HIF) in a subject, the method comprising administering to thesubject a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, or a pharmaceutical compositiondisclosed herein. In some embodiments, the HIF is HIF-1α.

In some embodiments of a method disclosed herein, the method furthercomprises administration of an additional active agent.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “some embodiments” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. Thus, the appearances of the phrases “in oneembodiment” or “in an embodiment” in various places throughout thisspecification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments. Also, asused in this specification and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the content clearlydictates otherwise. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“oxo” refers to ═O.

“Carboxyl” refers to —COOH.

“Cyano” refers to —CN.

“Alkyl” refers to a straight-chain, or branched-chain saturatedhydrocarbon monoradical having from one to about ten carbon atoms, morepreferably one to six carbon atoms. Examples include, but are notlimited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, suchas heptyl, octyl and the like. Whenever it appears herein, a numericalrange such as “C₁-C₆ alkyl” or “C₁₋₆alkyl”, means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms or 6 carbon atoms, although the present definitionalso covers the occurrence of the term “alkyl” where no numerical rangeis designated. In some embodiments, the alkyl is a C₁₋₁₀alkyl. In someembodiments, the alkyl is a C₁₋₆alkyl. In some embodiments, the alkyl isa C₁₋₅alkyl. In some embodiments, the alkyl is a C₁₋₄alkyl. In someembodiments, the alkyl is a C₁₋₃alkyl. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkyl is optionallysubstituted with halogen, —CN, —OH, or —OMe. In some embodiments, thealkyl is optionally substituted with halogen.

“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbonmonoradical having one or more carbon-carbon double-bonds and havingfrom two to about ten carbon atoms, more preferably two to about sixcarbon atoms. The group may be in either the cis or trans conformationabout the double bond(s), and should be understood to include bothisomers. Examples include, but are not limited to ethenyl (—CH═CH₂),1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)═CH₂], butenyl,1,3-butadienyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” or “C₂₋₆alkenyl”, means that the alkenylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkenyl” where no numerical range isdesignated. Unless stated otherwise specifically in the specification,an alkenyl group may be optionally substituted, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the alkenyl is optionally substituted withoxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkenyl is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkenyl is optionally substitutedwith halogen.

“Alkynyl” refers to a straight-chain or branched-chain hydrocarbonmonoradical having one or more carbon-carbon triple-bonds and havingfrom two to about ten carbon atoms, more preferably from two to aboutsix carbon atoms. Examples include, but are not limited to ethynyl,2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appearsherein, a numerical range such as “C₂-C₆ alkynyl” or “C₂₋₆alkynyl”,means that the alkynyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkynyl”where no numerical range is designated. Unless stated otherwisespecifically in the specification, an alkynyl group may be optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkynyl is optionallysubstituted with halogen, —CN, —OH, or —OMe. In some embodiments, thealkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain.Unless stated otherwise specifically in the specification, an alkylenegroup may be optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the alkylene is optionally substituted withoxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkylene is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkylene is optionallysubstituted with halogen.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, the alkoxy is optionallysubstituted with halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH₂, or —NO₂.In some embodiments, the alkoxy is optionally substituted with halogen,—CN, —OH, or —OMe. In some embodiments, the alkoxy is optionallysubstituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising 6 to 30 carbon atoms and at least one aromatic ring. The arylradical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem, which may include fused (when fused with a cycloalkyl orheterocycloalkyl ring, the aryl is bonded through an aromatic ring atom)or bridged ring systems. In some embodiments, the aryl is a 6- to10-membered aryl. In some embodiments, the aryl is a 6-membered aryl(phenyl). Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of anthrylene, naphthylene,phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, an aryl may beoptionally substituted, for example, with halogen, amino, nitrile,nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or—NO₂. In some embodiments, the aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments,the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a partially or fully saturated, monocyclic, orpolycyclic carbocyclic ring, which may include fused (when fused with anaryl or a heteroaryl ring, the cycloalkyl is bonded through anon-aromatic ring atom), spiro, or bridged ring systems. In someembodiments, the cycloalkyl is fully saturated. Representativecycloalkyls include, but are not limited to, cycloalkyls having fromthree to fifteen carbon atoms (e.g., C₃-C₁₅ fully saturated cycloalkylor C₃-C₁₅ cycloalkenyl), from three to ten carbon atoms (e.g., C₃-C₁₀fully saturated cycloalkyl or C₃-C₁₀ cycloalkenyl), from three to eightcarbon atoms (e.g., C₃-C₈ fully saturated cycloalkyl or C₃-C₈cycloalkenyl), from three to six carbon atoms (e.g., C₃-C₆ fullysaturated cycloalkyl or C₃-C₆ cycloalkenyl), from three to five carbonatoms (e.g., C₃-C₅ fully saturated cycloalkyl or C₃-C₅ cycloalkenyl), orthree to four carbon atoms (e.g., C₃-C₄ fully saturated cycloalkyl orC₃-C₄ cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to10-membered fully saturated cycloalkyl or a 3- to 10-memberedcycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-memberedfully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In someembodiments, the cycloalkyl is a 5- to 6-membered fully saturatedcycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, forexample, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane,bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, andbicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partiallysaturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically inthe specification, a cycloalkyl is optionally substituted, for example,with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, acycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl,—CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl,—CN, —CF₃, —OH, or —OMe. In some embodiments, the cycloalkyl isoptionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more hydroxyls. In some embodiments, the alkyl issubstituted with one hydroxyl. In some embodiments, the alkyl issubstituted with one, two, or three hydroxyls. Hydroxyalkyl include, forexample, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, orhydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Aminoalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more amines. In some embodiments, the alkyl issubstituted with one amine. In some embodiments, the alkyl issubstituted with one, two, or three amines. Aminoalkyl include, forexample, aminomethyl, aminoethyl, aminopropyl, aminobutyl, oraminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof. A heteroalkyl is attached to the rest of themolecule at a carbon atom of the heteroalkyl. In one aspect, aheteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprisedof 1 to 6 carbon atoms and one or more atoms other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof wherein the heteroalkyl is attached to the rest ofthe molecule at a carbon atom of the heteroalkyl. Examples of suchheteroalkyl are, for example, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃,—CH(CH₃)OCH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NHCH₃, or —CH₂CH₂N(CH₃)₂.Unless stated otherwise specifically in the specification, a heteroalkylis optionally substituted for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a heteroalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroalkyl isoptionally substituted with halogen.

“Heterocycloalkyl” refers to a 3- to 24-membered partially or fullysaturated ring radical comprising 2 to 23 carbon atoms and from one to 8heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous, silicon, and sulfur. In some embodiments, theheterocycloalkyl is fully saturated. In some embodiments, theheterocycloalkyl comprises one to three heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur. In some embodiments,the heterocycloalkyl comprises one to three heteroatoms selected fromthe group consisting of nitrogen and oxygen. In some embodiments, theheterocycloalkyl comprises one to three nitrogens. In some embodiments,the heterocycloalkyl comprises one or two nitrogens. In someembodiments, the heterocycloalkyl comprises one nitrogen. In someembodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include fused (when fused with anaryl or a heteroaryl ring, the heterocycloalkyl is bonded through anon-aromatic ring atom), spiro, or bridged ring systems; and thenitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized.Representative heterocycloalkyls include, but are not limited to,heterocycloalkyls having from two to fifteen carbon atoms (e.g., C₂-C₁₅fully saturated heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl), from twoto ten carbon atoms (e.g., C₂-C₁₀ fully saturated heterocycloalkyl orC₂-C₁₀ heterocycloalkenyl), from two to eight carbon atoms (e.g., C₂-C₈fully saturated heterocycloalkyl or C₂-C₈ heterocycloalkenyl), from twoto seven carbon atoms (e.g., C₂-C₇ fully saturated heterocycloalkyl orC₂-C₇ heterocycloalkenyl), from two to six carbon atoms (e.g., C₂-C₆fully saturated heterocycloalkyl or C₂-C₆ heterocycloalkenyl), from twoto five carbon atoms (e.g., C₂-C₅ fully saturated heterocycloalkyl orC₂-C₅ heterocycloalkenyl), or two to four carbon atoms (e.g., C₂-C₄fully saturated heterocycloalkyl or C₂-C₄ heterocycloalkenyl). Examplesof such heterocycloalkyl radicals include, but are not limited to,aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl,methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The termheterocycloalkyl also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides, andthe oligosaccharides. In some embodiments, heterocycloalkyls have from 2to 10 carbons in the ring. It is understood that when referring to thenumber of carbon atoms in a heterocycloalkyl, the number of carbon atomsin the heterocycloalkyl is not the same as the total number of atoms(including the heteroatoms) that make up the heterocycloalkyl (i.e.skeletal atoms of the heterocycloalkyl ring). In some embodiments, theheterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In someembodiments, the heterocycloalkyl is a 3- to 7-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 4- to 6-membered heterocycloalkyl. In some embodiments, theheterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In someembodiments, the heterocycloalkyl is a 3- to 8-memberedheterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkylis a 3- to 6-membered heterocycloalkenyl. In some embodiments, theheterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In someembodiments, the heterocycloalkyl is a 5- to 6-memberedheterocycloalkenyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl may be optionally substituted asdescribed below, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the heterocycloalkyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF₃,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the heterocycloalkyl isoptionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or—OMe. In some embodiments, the heterocycloalkyl is optionallysubstituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising one to thirteen carbon atoms, one to six heteroatoms selectedfrom the group consisting of nitrogen, oxygen, phosphorous, and sulfur,and at least one aromatic ring. In some embodiments, the heteroarylcomprises one to three heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. In some embodiments, the heteroarylcomprises one to three heteroatoms selected from the group consisting ofnitrogen and oxygen. In some embodiments, the heteroaryl comprises oneto three nitrogens. In some embodiments, the heteroaryl comprises one ortwo nitrogens. In some embodiments, the heteroaryl comprises onenitrogen. The heteroaryl radical may be a monocyclic, bicyclic,tricyclic, or tetracyclic ring system, which may include fused (whenfused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl isbonded through an aromatic ring atom) or bridged ring systems; and thenitrogen, carbon, or sulfur atoms in the heteroaryl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized. Insome embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. Insome embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Insome embodiments, the heteroaryl is a 6-membered heteroaryl. In someembodiments, the heteroaryl is a 5-membered heteroaryl. Examplesinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl,1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl may be optionallysubstituted, for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the heteroaryl is optionally substituted with halogen,methyl, ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, the heteroaryl is optionally substituted with halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, theheteroaryl is optionally substituted with halogen.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

The term “one or more” when referring to an optional substituent meansthat the subject group is optionally substituted with one, two, three,four, or more substituents. In some embodiments, the subject group isoptionally substituted with one, two, three or four substituents. Insome embodiments, the subject group is optionally substituted with one,two, or three substituents. In some embodiments, the subject group isoptionally substituted with one or two substituents. In someembodiments, the subject group is optionally substituted with onesubstituent. In some embodiments, the subject group is optionallysubstituted with two substituents.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition.

Compounds

Described herein are compounds of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof useful in thetreatment of inflammatory bowel disease (IBD).

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

-   wherein:-   R¹ is monocyclic heterocycloalkyl which is optionally and    independently substituted;-   X is N or CR²;-   R² is hydrogen, fluoro, chloro, bromo, —CN, —NO₂, —OH, —OR^(a),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   R³ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁴ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   Y is —O—, —S—, or —NR⁶—;-   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   L is —(CR⁷R⁸)_(p);-   each R⁷ and R⁸ are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   or R⁷ and R⁸ on the same carbon are taken together to form a    cycloalkyl or heterocycloalkyl; each optionally substituted with one    or more R^(7a);-   each R^(7a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   p is 0-4;-   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R⁹ is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    optionally and independently substituted;-   n is 0-4;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted;-   each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted; and-   each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted;-   or R^(c) and R^(d) are taken together with the atom to which they    are attached to form an optionally substituted heterocycloalkyl.

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

-   wherein:-   R¹ is monocyclic heterocycloalkyl optionally and independently    substituted with one or more R^(1a);-   each R^(1a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(1a) on the same atom are taken together to form an oxo;-   X is N or CR²;-   R² is hydrogen, fluoro, chloro, bromo, —CN, —NO₂, —OH, —OR^(a),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   R³ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁴ is hydrogen, halogen, —CN, —NO₂, —OH, —OR^(a), —C(═O)R^(a),    —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; Y is —O—, —S—, or —NR⁶—;-   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   L is —(CR⁷R⁸)_(p);-   each R⁷ and R⁸ are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   or R⁷ and R⁸ on the same carbon are taken together to form a    cycloalkyl or heterocycloalkyl; each optionally substituted with one    or more R^(7a);-   each R^(7a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   p is 0-4;-   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R⁹ is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    optionally and independently substituted with one or more R^(9a);-   or two R⁹ on the same atom are taken together to form an oxo;-   each R^(9a) is independently halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)RR, —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(9a) on the same atom are taken together to form an oxo;-   n is 0-4;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    R;-   each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    R; and-   each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more R;-   or R^(c) and R^(d) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more R; and-   each R is independently halogen, —CN, —OH,—OC₁-C₆alkyl,    —S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂,    —S(═O)₂NHC₁-C₆alkyl, —S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl,    —N(C₁- C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —C(═O)OH,    —C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂,    —C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or two R on the same atom are    taken together to form an oxo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is N. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is CR².

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R² is hydrogen,fluoro, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R² is hydrogen or C₁-C₆alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R² is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is hydrogen,halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is hydrogen, halogen, or C₁-C₆alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is hydrogen orC₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ is hydrogen,halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁴ is hydrogen, halogen, or C₁-C₆alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ is hydrogen orC₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁵ is hydrogen orC₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵is C₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —O— or —NR⁶—. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —NR⁶—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —O—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —S—.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶ is hydrogen orC₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶is C₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 1-4. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 1-3. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 1. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, p is 3.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R⁷ and R⁸ areindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl; or R⁷ and R⁸ on the same carbon are taken together toform a cycloalkyl or heterocycloalkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R⁷ and R⁸ are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁷ and R⁸ on the same carbon are takentogether to form a cycloalkyl or heterocycloalkyl. In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R⁷ and R⁸ are independentlyhydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R⁷ and R⁸ are hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(7a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(7a) is independently halogen, —OH, —OR^(a), C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Ring A is aryl orheteroaryl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, RingA is phenyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, RingA is 5- or 6-membered heteroaryl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Ring A is 6-membered heteroaryl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Ring A is 6-memberedpyridyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 1-3. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 2-4. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 2 or 3. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 1 or 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 0. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 1. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, n is 3.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R⁹ isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R⁹ isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R⁹ isindependently halogen or —CN.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R⁹ is —CN.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is monocyclicheterocycloalkyl independently substituted with one or more R^(1a). Insome embodiments, R¹ is independently substituted with 1, 2, 3, or 4R^(1a). In some embodiments, R¹ is independently substituted with 1 or 2R^(1a). In some embodiments, R¹ is substituted monocyclicheterocycloalkyl.

In some embodiments, R¹ is a 4 membered, optionally substitutedmonocyclic heterocycloalkyl. In some embodiments, R¹ is a 5 membered,optionally substituted monocyclic heterocycloalkyl. In some embodiments,R¹ is a 6 membered, optionally substituted monocyclic heterocycloalkyl.In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is attached to therest of the fragment of formula (I) via a nitrogen atom of R¹. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

each of which is optionally substituted with one or more R^(1a). In someembodiments, R¹ is

which is optionally substituted with 1 or 2 R^(1a). In some embodiments,R¹ is

which is optionally substituted with 1 or 2 R^(1a). In some embodiments,R¹ is

which is optionally substituted with 1 or 2 R^(1a). In some embodiments,R¹ is

which is optionally substituted with 1 or 2 R^(1a).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionallyand independently substituted with one or more R^(1a).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is piperidinyloptionally substituted with one or more R^(1a).

In some embodiments, R¹ is monocyclic heterocycloalkyl optionally andindependently substituted with 1 or 2 R^(1a). In some embodiments, R¹ is5-7 membered (e.g., 6 membered) monocyclic heterocycloalkyl optionallyand independently substituted with 1 or 2 R^(1a), and wherein themonocyclic heterocycloalkyl contains 1-3 ring nitrogen atoms.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is unsubstituted.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(1a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R^(1a) on thesame atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(1a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; ortwo R^(1a) on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(1a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—NR^(b)C(═O)R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R^(1a) on thesame atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(1a) isindependently halogen, —OH, —OR^(a), —NR^(b)C(═O)R^(a), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆heteroalkyl, or cycloalkyl; or two R^(1a) on thesame atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(1a) isindependently C₁-C₆alkyl (e.g., methyl), C₁-C₆haloalkyl, or —C(═O)OR^(b)(e.g., —C(═O)O(C₁-C₆alkyl)).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(1a) is—C(═O)NR^(c)R^(d). In some embodiments of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(1a) is —C(═O)NH₂. In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(1a) is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(a) isindependently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more R. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(a) is independently C₁-C₆alkyl,C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more R. In some embodiments of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), orC₁-C₆alkylene(heteroaryl). In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl, orcycloalkyl, heterocycloalkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(a) is independently C₁-C₆alkyl orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(a) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more R. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(b) is independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more R. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) is independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl). In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(b) is independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(b) isindependently hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(b) isindependently hydrogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) is hydrogen. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(b) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(c) and R^(d)are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), orC₁-C₆alkylene(heteroaryl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more R. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(c) and R^(d) are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more R. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(c) and R^(d) are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl). In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(c) and R^(d) are independentlyhydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl.In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(c) and R^(d)are independently hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(c) and R^(d)are independently hydrogen or C₁-C₆alkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(c) and R^(d) are hydrogen. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(c) and R^(d)are independently C₁-C₆alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(c) is hydrogen, C₁-C₆hydroxyalkyl, C₁-C₆alkyl,C₁-C₆aminoalkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(d) is hydrogen, C₁-C₆hydroxyalkyl, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl,heterocycloalkyl, C₁-C₆alkylene(cycloalkyl), orC₁-C₆alkylene(heterocycloalkyl). In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(d) is —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂CH₂OCH₂CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂CH₂OH, or —CH₂CH₂NHC(═O)O-t-butyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(c) and R^(d) aretaken together with the atom to which they are attached to form aheterocycloalkyl optionally substituted with one or more R.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R isindependently halogen, —CN, —OH,—OC₁-C₆alkyl, —NH₂,—NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —C(═O)OH,—C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂, —C(═O)NHC₁-C₆alkyl,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R is independently halogen, —CN,—OH,—OC₁-C₆alkyl, —NH₂, —C(═O)C₁-C₆alkyl, —C(═O)OH, —C(═O)OC₁-C₆alkyl,—C(═O)NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R is independently halogen, —CN, —OH,—OC₁-C₆alkyl, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound disclosed herein, each R¹, R⁹, R^(a),R^(b), R^(c), R^(d), the heterocycloalkyl formed when R⁷ and R⁸ aretaken together, and the heterocycloalkyl formed when R^(c) and R^(d) aretaken together, is optionally and independently substituted with one,two, three, or four substituents as defined herein. In some embodimentsof a compound disclosed herein, each R¹, R⁹, R^(a), R^(b), R^(c), R^(d),the heterocycloalkyl formed when R⁷ and R⁸ are taken together, and theheterocycloalkyl formed when R^(c) and R^(d) are taken together, isoptionally and independently substituted with one, two, or threesubstituents as defined herein. In some embodiments of a compounddisclosed herein, each R¹, R⁹, R^(a), R^(b), R^(c), R^(d), theheterocycloalkyl formed when R⁷ and R⁸ are taken together, and theheterocycloalkyl formed when R^(c) and R^(d) are taken together, isoptionally and independently substituted with one or two substituents asdefined herein. In some embodiments of a compound disclosed herein, eachR¹, R⁹, R^(a), R^(b), R^(c), R^(d), the heterocycloalkyl formed when R⁷and R⁸ are taken together, and the heterocycloalkyl formed when R^(c)and R^(d) are taken together, is optionally and independentlysubstituted with one substituent as defined herein.

In some embodiments of a compound disclosed herein, the abundance ofdeuterium in each of R, R¹, R^(1a), R², R³, R⁴, R⁵, R⁶, R⁷, R^(7a), R⁸,R⁹, R^(9a), R^(a), R^(b), R^(c), and/or R^(d) is independently at least1%, at least 10% at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, at least 70%, at least 80%, at least 90%, or 100% of atotal number of hydrogen and deuterium.

In some embodiments of a compound disclosed herein, one or more of R,R¹, R^(1a), R², R³, R⁴, R⁵, R⁶, R⁷, R^(7a), R⁸, R⁹, R^(9a), R^(a),R^(b), R^(c), and/or R^(d) groups comprise deuterium at a percentagehigher than the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or morehydrogens are replaced with one or more deuteriums in one or more of thefollowing groups R, R¹, R^(1a), R², R³, R⁴, R⁵, R⁶, R⁷, R^(7a), R⁸, R⁹,R^(9a), R^(a), R^(b), R^(c), and/or R^(d).

In some embodiments of a compound disclosed herein, one or morehydrogens of Ring A are replaced with one or more deuteriums.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, is one of thecompounds in Table 1.

TABLE 1 Ex. Structure 3

4

5

6

7

9

10

15

16

17

18

19

20

21

22

23

24

26

27

28

29

31

32

33

34

35

36

37

38

39

40

41

42

45

46

47

48

50

51

57

59

60

63

64

65

66

70

71

72

73

74

75

84

85

86

89

92

94

95

96

100

101

102

103

112

113

114

119

120

121

123

124

125

126

127

128

132

133

134

135

136

137

138

139

140

142

143

144

149

150

151

152

153

154

155

156

157

158

160

163

Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent, by any practical means that would notresult in racemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds disclosed herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, andchloride, such as ²H (D), ³H (T), ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F and ³⁶Cl, respectively. Compounds described herein, and thepharmaceutically acceptable salts, solvates, or stereoisomers thereofwhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14,i.e., ¹⁴C, isotopes are particularly preferred for their ease ofpreparation and detectability.

In some embodiments, the abundance of deuterium in each of thesubstituents disclosed herein is independently at least 1%, at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, or 100% of a total numberof hydrogen and deuterium. In some embodiments, one or more of thesubstituents disclosed herein comprise deuterium at a percentage higherthan the natural abundance of deuterium. In some embodiments, one ormore hydrogens are replaced with one or more deuteriums in one or moreof the substituents disclosed herein.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or a solvate, or stereoisomer thereof, or byseparately reacting a purified compound in its free form with a suitableacid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfate, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylateundeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds disclosed herein, solvate, or stereoisomerthereof and their pharmaceutically acceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulasdescribed herein. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH.

Method of Treatment

Disclosed herein is a method of treating a disease or disorder in asubject, the method comprising administering to the subject a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein the disease or disorder is inflammatorybowel disease (IBD). In some embodiments, the disease or disorder isulcerative colitis (“UC”) or Crohn's disease (“CD”). In someembodiments, the disease or disorder is ulcerative colitis (“UC”). Insome embodiments, the disease or disorder is Crohn's disease (“CD”).

Inflammatory Bowel Disease (IBD)

IBD is an umbrella term used to describe disorders that involve chronicinflammation of the digestive tract. Types of IBD include ulcerativecolitis (“UC”) and Crohn's disease (“CD”). IBD symptoms vary and dependon the severity of inflammation and the location it occurs. According toGlobalData, in 2019, there were 1.7 million diagnosed UC patients in 8major markets (US, 5EU, Japan and Canada) and the market sales reached$6.8 billion in that year. [In addition, there were 1.3 million UCdiagnosed prevalent population in 8 major markets (US, 5EU, Japan andCanada) and the market sales reach $7.4 billion.]

Inflammatory bowel diseases are characterized by repeated inflammationand wounding of the mucosa and loss of the intestinal epithelial barrierfunction, which lead to the passage of bacteria or bacterial productsfrom the gut lumen to the serosa and into the blood, resulting insystemic bacteremia and endotoxemia. PHD inhibition has been shown toreduce disease severity in murine models of colitis on several levels ofclinical scoring. The proposed mechanism for the therapeutic activity ofPHD inhibitors is through HIF-1α stabilization, which drives epithelialbarrier augmentation and healing.

Despite the efficacy of current treatment with anti-inflammation agentsor immune-suppressive agents, a large fraction of IBD patients do notrespond adequately to currently available therapies and do not achievelong-term remission. Inhibitors of PHDs may provide a new therapeuticoption for IBD and may be combined with available anti-inflammatorydrugs to achieve an enhanced efficacy.

Dosing

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder, or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of or riskfactor for the disease being treated and is currently in remission, apharmaceutical composition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10% 100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage, or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent or daily treatment on along-term basis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage, or the amount of active in the dosage form are loweror higher than the ranges indicated herein, based on a number ofvariables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₁₀ and the ED₉₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the subject every 12 hours; (v) the compound isadministered to the subject every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated with organspecific antibody. In such embodiments, the liposomes are targeted toand taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions/Formulations

The compounds described herein are administered to a subject in needthereof, either alone or in combination with pharmaceutically acceptablecarriers, excipients, or diluents, in a pharmaceutical composition,according to standard pharmaceutical practice. In one embodiment, thecompounds may be administered to animals. The compounds can beadministered orally or parenterally, including the intravenous,intramuscular, intraperitoneal, subcutaneous, rectal, and topical routesof administration.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, and at least onepharmaceutically acceptable excipient. Pharmaceutical compositions areformulated in a conventional manner using one or more pharmaceuticallyacceptable excipients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

In some embodiments, the pharmaceutically acceptable excipient isselected from carriers, binders, filling agents, suspending agents,flavoring agents, sweetening agents, disintegrating agents, dispersingagents, surfactants, lubricants, colorants, diluents, solubilizers,moistening agents, plasticizers, stabilizers, penetration enhancers,wetting agents, anti-foaming agents, antioxidants, preservatives, andany combinations thereof.

The pharmaceutical compositions described herein are administered to asubject by appropriate administration routes, including, but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, self-emulsifying dispersions, solidsolutions, liposomal dispersions, aerosols, solid oral dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, powders,dragees, effervescent formulations, lyophilized formulations, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including compounds described herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, or compressionprocesses.

Pharmaceutical compositions for oral use are obtained by mixing one ormore solid excipient with one or more of the compounds described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active compound doses.

Pharmaceutical compositions that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds are dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

Pharmaceutical compositions for parental use are formulated as infusionsor injections. In some embodiments, the pharmaceutical compositionsuitable for injection or infusion includes sterile aqueous solutions,or dispersions, or sterile powders comprising a compound describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof. In some embodiments, the pharmaceutical composition comprises aliquid carrier. In some embodiments, the liquid carrier is a solvent orliquid dispersion medium comprising, for example, water, saline,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and any combinations thereof. In some embodiments, thepharmaceutical compositions further comprise a preservative to preventgrowth of microorganisms.

Combination

Disclosed herein are methods of treating inflammatory bowel disease(IBD) using a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, in combination withan additional therapeutic agent.

In some embodiments, the additional therapeutic agent is administered atthe same time as the compound disclosed herein. In some embodiments, theadditional therapeutic agent and the compound disclosed herein areadministered sequentially. In some embodiments, the additionaltherapeutic agent is administered less frequently than the compounddisclosed herein. In some embodiments, the additional therapeutic agentis administered more frequently than the compound disclosed herein. Insome embodiments, the additional therapeutic agent is administered priorthan the administration of the compound disclosed herein. In someembodiments, the additional therapeutic agent is administered after theadministration of the compound disclosed herein.

In some embodiments, the additional therapeutic agent is acardiovascular agent such as calcium channel blockers, includingamlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine,nifedipine, nisoldipine, and verapamil; statins, including atorvastatin,fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, andpitavastatin; a fibrate, including gemfibrozil and fenofibrate;beta-blockers, including acebutolol, atenolol, betaxolol, bisoprolol,carvedilol, esmolol, labetalo metoprolol, nadolol, nebivolol,penbutolol, propranolol, sotalol, and timolol; an ACE inhibitor,including benazepril, captopril, enalapril, fosinopril, lisinopril,moexipril, perindopril, quinapril, ramipril, and trandolapril; andplatelet aggregation inhibitors, including aspirin, cangrelor,clopidogrel, cilostazol, dipyridamole, prasugrel, and ticagrelor.

In some embodiments, the additional therapeutic agent is an agent fortreating metabolic disorders. These agents include pancreatic lipaseinhibitors (e.g., orlistat); insulin; insulin sensitizers, includingbiguanides (e.g., buformin, metformin, and phenformin) and glitazones(e.g., pioglitazone and rosiglitazone); insulin secretagogues, includingsulfonylureas (e.g., acetohexamide, chlorpropamide, tolazamide,tolbutamide, gliclazide, glimepiride, glipizide, and glyburide), andmeglitinides (e.g., nateglinide and repaglinide); alpha-glucosidaseinhibitors (e.g., acarbose and miglitol); glucagon-like peptide analogsand agonists (e.g., exenatide, liraglutide, and taspoglutide);dipeptidyl peptidase-4 inhibitors (e.g., alogliptin, linagliptin,saxagliptin, sitagliptin, and vildagliptin); and amylin analogs (e.g.,pramlinitide).

In some embodiments, the additional therapeutic agent is an agent fortreating wound healing disorders. In some embodiments, the additionaltherapeutic agent is an anti-inflammatory agent, analgesics, anantipruritic, or an anti-infective.

Examples of anti-inflammatory agents include nonsteroidalanti-inflammatory drugs (NSAIDs) and corticosteroids. RepresentativeNSAIDs include apazone, aspirin, celecoxib, diclofenac (with and withoutmisoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam,choline and magnesium salicylates, salsalate, and sulindac.Representative corticosteroids include betamethasone, cortisone acetate,dexamethasone, hydrocortisone, methylprednisolone, prednisolone, andprednisone. Representative analgesics include acetaminophen and morphinesulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene, andtramadol, all with or without acetaminophen. Representativeantipruritics for systemic use include cyproheptadine, diphenhydramine,gabapentin, hydroxyzine, and ondansetron.

Representative antipruritics for topical use include ammonium lactate,benzocaine, calamine, capsaicin, clioquinol, crotamiton,diphenhydramine, doxepin, hydrocortisone, lidocaine, menthol, methylsalicylate, and pramoxine.

Example anti-infective agents may include antibacterials, antifungals,and antivirals.

Representative antibacterials include aminoglycosides, such as amikacin,gentamicin, kanamycin, neomycin, paromomycin, and tobramycin;carbapenems, such as doripenem, ertapenem, imipenem, and meropenem;cephalosporins, including combinations with beta-lactamase inhibitorssuch as ceftazidime/avibactam and ceftolozane/tazobactam;first-generation cephalosporins, such as cefadroxil, cefazolin,cephalexin, and cephradine; second-generation cephalosporins, such ascefotetan, cefprozil, cefuroxime, efoxitin, and loracarbef;third-generation cephalosporins, such as cefdinir, cefditoren, cefixime,cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,ceftizoxime, and ceftriaxone; and fourth- and next-generationcephalosporins, such as cefepime and ceftaroline; glycopeptideantibiotics, such as dalbavancin, oritavancin, telavancin, andvancomycin; glycylcyclines, such as tigecycline; lincomycin and itsderivatives, such as clindamycin; macrolides, such as azithromycin,clarithromycin, erythromycin, and fidaxomicin, and macrolidederivatives, including ketolides such as telithromycin; oxazolidinoneantibiotics, such as linezolid and tedizolid; penicillins, includingaminopenicillins, such as amoxicillin and ampicillin; antipseudomonalpenicillins, such as carbenicillin, piperacillin, and ticarcillin;penicillins with beta-lactamase inhibitors such asamoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate; natural penicillins, such as penicillin Gbenzathine, penicillin V potassium, and procaine penicillin;penicillinase resistant penicillins, such as dicloxacillin, nafcillin,and oxacillin; quinolones, such as cinoxacin, ciprofloxacin,delafloxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin,moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, andtrovafloxacin; sulfonamides, such as sulfamethoxazole/trimethoprim andsulfisoxazole; tetracycline and its derivatives, such as demeclocycline,doxycycline, doxycycline/omega-3 polyunsaturated fatty acids,doxycycline/salicylic acid, minocycline, and oxytetracycline. Otherrepresentative antibacterials include atovaquone, aztreonam, bacitracin,chloramphenicol, colistimethate, dalfopristin/quinupristin, daptomycin,erythromycin/sulfisoxazole, fosfomycin, metronidazole, pentamidine,rifaximin, spectinomycin, and trimetrexate.

Representative antifungals include azole antifungals, such asclotrimazole, fluconazole, isavuconazonium, itraconazole, ketoconazole,miconazole, posaconazole, and voriconazole; echinocandins, such asanidulafungin, caspofungin, and micafungin; and polyenes, such asamphotericin B, amphotericin B cholesteryl sulfate, amphotericin B lipidcomplex, and nystatin. Other representative antifungals includeflucytosine, griseofulvin, and terbinafine

Representative antiviral agents include purine nucleosides, such asacyclovir, cidofovir, famciclovir, ganciclovir, ribavirin, valacyclovir,and valganciclovir.

In some embodiments, the additional therapeutic agent is an anti-canceragent. In some embodiments, the additional therapeutic agent is achemotherapeutic agent (i.e., cytotoxic, or antineoplastic agents) suchas alkylating agents, antibiotics, antimetabolic agents, plant-derivedagents, and topoisomerase inhibitors, as well as molecularly targeteddrugs which block the growth and spread of cancer by interfering withspecific molecules involved in tumor growth and progression. Molecularlytargeted drugs include both small molecules and biologics.

Representative alkylating agents include bischloroethylamines (nitrogenmustards) including chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, and uracil mustard); aziridines, includingthiotepa; alkyl alkone sulfonates, including busulfan; nitrosoureas,including carmustine, lomustine, and streptozocin; nonclassicalalkylating agents, including altretamine, dacarbazine, and procarbazine;and platinum compounds, including carboplatin, cisplatin, nedaplatin,oxaliplatin, satraplatin, and triplatin tetranitrate.

Representative antibiotic agents include anthracyclines, includingaclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones,including mitoxantrone and pixantrone; and Streptomyces, includingactinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin.

Representative antimetabolic agents include dihydrofolate reductaseinhibitors, including aminopterin, methotrexate, and pemetrexed;hymidylate synthase inhibitors, including raltitrexed and pemetrexed;folinic acid, including leucovorin; adenosine deaminase inhibitors,including pentostatin; halogenated/ribonucleotide reductase inhibitors,including cladribine, clofarabine, and fludarabine; thiopurines,including thioguanine and mercaptopurine; thymidylate synthaseinhibitors, including fluorouracil, capecitabine, tegafur, carmofur, andfloxuridine; DNA polymerase inhibitors, including cytarabine;ribonucleotide reductase inhibitors, including gemcitabine;hypomethylating agent, including azacitidine and decitabine;ribonucleotide reductase inhibitor, including hydroxyurea; and anasparagine deplete, including asparaginase.

Representative plant-derived agents include vinca alkaloids, includingvincristine, vinblastine, vindesine, vinzolidine, and vinorelbine;podophyllotoxins, including etoposide and teniposide; and taxanes,including docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel.

Representative type I topoisomerase inhibitors include camptothecins,including belotecan, irinotecan, rubitecan, and topotecan.Representative type II topoisomerase inhibitors include amsacrine,etoposide, etoposide phosphate, and teniposide, which are derivatives ofepipodophyllotoxins.

Molecularly targeted therapies include biologic agents such as cytokinesand other immune-regulating agents. Useful cytokines includeinterleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4), interleukin 12(IL-12), and interferon, which includes more than 23 related subtypes.Other cytokines include granulocyte colony stimulating factor (CSF)(filgrastim) and granulocyte macrophage CSF (sargramostim). Otherimmuno-modulating agents include bacillus Calmette-Guerin, levamisole,and octreotide; monoclonal antibodies against tumor antigens, such astrastruzumab and rituximab; and cancer vaccines, which induce an immuneresponse to tumors.

In addition, molecularly targeted drugs that interfere with specificmolecules involved in tumor growth and progression include inhibitors ofepidermal growth factor (EGF), transforming growth factor-alpha(TGF_(a)), TGFp, heregulin, insulin-like growth factor (IGF), fibroblastgrowth factor (FGF), keratinocyte growth factor (KGF), colonystimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2),nerve growth factor (NGF), platelet-derived growth factor (PDGF),hetaptocyte growth factor (HGF), vascular endothelial growth factor(VEGF), angiopoietin, epidermal growth factor receptor (EGFR), humanepidermal growth factor receptor 2 (HER2), HER4, insulin-like growthfactor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor(FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth factorreceptor (VEGFR), tyrosine kinase with immunoglobulin-like and epidermalgrowth factor-like domains 2 (Tie-2), platelet-derived growth factorreceptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3),c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk),Ret, mammalian target of rapamycin (mTOR), Aurora kinase, polo-likekinase (PLK), mitogen activated protein kinase (MEK),mesenchymal-epithelial transition factor (c-MET), cyclin-dependantkinase (CDK), Akt, extracellular signal-regulated kinases (ERK),poly(ADP) ribose polymerase (PARP), and the like.

Specific molecularly targeted drugs include selective estrogen receptormodulators, such as tamoxifen, toremifene, fulvestrant, and raloxifene;antiandrogens, such as bicalutamide, nilutamide, megestrol, andflutamide; and aromatase inhibitors, such as exemestane, anastrozole,and letrozole. Other specific molecularly targeted drugs include agentswhich inhibit signal transduction, such as imatinib, dasatinib,nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib,panitumumab, and temsirolimus; agents that induce apoptosis, such asbortezomib; agents that block angiogenesis, such as bevacizumab,sorafenib, and sunitinib; agents that help the immune system destroycancel cells, such as rituximab and alemtuzumab; and monoclonalantibodies which deliver toxic molecules to cancer cells, such asgemtuzumab ozogamicin, tositumomab, 131I-tositumoab, and ibritumomabtiuxetan.

EXAMPLES Intermediate A: Synthesis of methyl2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate

Step 1

To a mixture of methyl (E)-3-aminobut-2-enoate (10 g, 87 mmol) in MeOH(100 mL) was added methyl prop-2-ynoate (7.78 g, 92.6 mmol). The mixturewas stirred at 70° C. for 12 h. The mixture was cooled to 5° C. Theprecipitate was filtered triturated with MTBE (50 mL×3). Methyl6-hydroxy-2-methylnicotinate (5 g, 34% yield) was obtained as a whitesolid. NMR (400 MHz, CDCl₃) δ 12.61 (s, 1H), 8.02 (d, J=8 Hz, 1H), 6.42(d, J=12 Hz, 1H), 3.84 (s, 3H), 2.72 (s, 3H).

Step 2

A solution of mixture of methyl 6-hydroxy-2-methylnicotinate (5 g, 29.8mmol) in POCl₃ (17.7 g, 115 mmol) was stirred at 100° C. for 4 h. Thereaction was slowly poured into ice water (100 mL) and then extractedwith ethyl acetate (100 mL×2). The combined organic layers were washedwith NaHCO₃ (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude was used directly for the next step.

Step 3

To a solution of methyl 6-chloro-2-methylnicotinate (6 g, 32.4 mmol) inCCl₄ (60 mL) was added NBS (6.9 g, 38.7 mmol) and BPO (1.56 g, 6.45mmol). The mixture was stirred at 80° C. for 12 h. The reaction mixturewas diluted with DCM (60 mL) and washed with H₂O (60 mL×3). The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatograph to afford Methyl 2-(bromomethyl)-6-chloronicotinate as ayellow solid (11 g, crude). LCMS: RT=0.981 min; MS m/z (ESI)[M+H]⁺=264.1.

Step 4

To a solution of methyl 2-(bromomethyl)-6-chloronicotinate (5 g, 18.9mmol) and methyl 2-(p-tolylsulfonylamino) acetate (4.6 g, 18.9 mmol) inDMF (50 mL) was added K₂CO₃ (5.02 g, 47.4 mmol) and NaI (0.28 g, 1.86mmol). The mixture was stirred at 50° C. for 12 h under N₂ atmosphere.The reaction mixture was diluted with ethyl acetate (200 mL) and washedwith H₂O (80 mL×3). The organic layer was washed with brine (80 mL×3),dried over MgSO₄, filtered, and concentrated under reduced pressure togive a residue. The residue was purified by silica gel chromatograph toafford methyl6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)nicotinate(6 g, crude) as a yellow solid.

Step 5

To a solution of methyl6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)nicotinate(6 g, 14 mmol) in DMSO (60 mL) was added K₂CO₃ (11.6 g, 84.3 mmol). Themixture was stirred at 50° C. for 4 h under N₂ atmosphere. The mixturewas diluted with H₂O (60 mL) and the aqueous was adjusted pH to 6 with 1M HCl. The precipitated solid was filtered and dried to affordIntermediate A (1.5 g, 45% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.72 (d, J=0.9 Hz, 1H), 7.91 (d, J=8.8 Hz,1H), 3.95 (s, 3H).

General procedure A: The synthesis of tert-butyl4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate(Example 29)

Step 1

To a solution of Intermediate A (1 g, 4.19 mmol) in MeOH (30 mL) wereadded 5-(aminomethyl)pyridine-2-carbonitrile (0.84 g, 6.29 mmol), TEA(2.91 mL, 20.95 mmol), and the reaction was stirred at 75° C. overnight.The reaction mixture was filtered through normal funnel and the filtercake was washed with 10 mL MeOH, dried in vacuum to afford2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide,Intermediate B (1.1 g, 3.24 mmol, 77% yield) as a yellow solid.

Step 2

To a solution of Intermediate B (1.1 g, 3.24 mmol) in DMSO (15 mL) wereadded TEA (1.35 mL, 9.71 mmol), tert-butyl piperazine-1-carboxylate (904mg, 4.86 mmol), and the reaction was stirred at 100° C. for 2 h underN₂. The reaction was cooled and poured into water H₂O (200 mL). Themixture was extracted with EtOAc (50 mL×3). The combined organic layerwas washed with saturated NaCl solution (30 mL×3), and concentrated invacuo. The residue was triturated with CH₃CN (20 mL) and CH₂Cl₂ (5 mL)and filtered to afford Example 29 (500 mg, 1.02 mmol, 32% yield) as awhite solid. LCMS: RT=1.838 min; MS m/z (ESI) [M+H]⁺=490.1. ¹H NMR (400MHz, DMSO-d₆) δ 13.36 (s, 1H), 9.77 (t, J=6.3 Hz, 1H), 8.76 (s, 1H),8.44 (s, 1H), 8.29 (d, J=9.4 Hz, 1H), 8.00 (s, 2H), 7.48 (d, J=9.5 Hz,1H), 4.63 (d, J=6.3 Hz, 2H), 3.82-3.79 (m, 4H), 3.50-3.48 (m, 4H), 1.46(s, 9H).

General procedure C: The synthesis ofN-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide(Example 3)

Step 1

To a mixture of Intermediate A (300 mg, 1.26 mmol) and morpholine (76.67mg, 880.03 μmol, 77.44 μL) in THF (10 mL) was added DIEA (324.96 mg,2.51 mmol, 437.95 μL) at 25° C. The mixture was stirred at 50° C. for 17h. Morpholine (76.67 mg, 880.03 μmol, 77.44 μL) was added and themixture was stirred at 65° C. for 4.5 h. The mixture was concentratedunder reduced pressure. The residue was purified by flash silica gelchromatography to afford methyl5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylate (128 mg, 383.84μmol, 31% yield) as a white solid. LCMS: RT=0.637 min; MS m/z (ESI)[M+H]⁺=290.1.

Step 2

To a solution of methyl5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylate (128 mg, 442.47μmol) in THF (1.5 mL) and H₂O (1.5 mL) was added LiOH·H₂O (37.14 mg,884.94 μmol) at 25° C. The mixture was stirred at 25° C. for 16 h and at50° C. for another 3 h. The reaction mixture was concentrated andadjusted with HCl (1 M) to pH=6. Water (20 mL) was added, and themixture was extracted with EtOAc (20 mL×3). The aqueous was lyophilizedto afford 5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylic acid(130 mg, crude) as a yellow solid. LCMS: RT=0.525 min; MS m/z (ESI)[M+H]⁺=276.1.

Step 3

To a mixture of carboxylic acid (45 mg, 163.48 μmol) and TEA (49.63 mg,490.45 μmol, 68.26 μL) in DMF (1 mL) was added HATU (68.38 mg, 179.83μmol) at 25° C. The mixture was stirred at 25° C. for 1 h. Then amine(32.68 mg, 196.18 μmol) was added and the mixture was stirred at 25° C.for 2 h. Two drops of water were added. The mixture was filtered. Thefiltrate was purified by prep-HPLC and lyophilized to afford theproduct, which was combined with another batch of the product (6.0 mg)and lyophilized to afford Example 3 (10.78 mg, 25.15 μmol, 6% yield) asa white solid. LCMS: RT=0.831 min; MS m/z (ESI) [M+H]⁺=424.1. ¹H NMR(400 MHz, DMSO-d₆) δ=13.31 (s, 1H), 9.76-9.68 (m, 1H), 8.47 (s, 1H),8.29 (d, J=9.6 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.85-7.76 (m, 1H),7.55-7.46 (m, 2H), 4.63 (d, J=6.4 Hz, 2H), 3.80-3.70 (m, 8H).

General procedure D: The synthesis ofN-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(Example 5)

Step 1

To a solution of Intermediate A (500 mg, 2.10 mmol) and tert-butylpiperazine-1-carboxylate (467.5 mg, 2.52 mmol) in anhydrous DMSO (5 mL)was added TEA (525 mg, 5.25 mmol). The solution was stirred at 100° C.for 16 h under N₂. The reaction mixture was poured into H₂O (30 mL) andextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by flash silica gelchromatography. Methyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate(200 mg, 25% yield) was obtained as a yellow solid. LCMS: RT=1.002 min;MS m/z (ESI) [M+H]⁺=389.0.

Step 2

To a solution of methyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate(100 mg, 0.295 mmol) and 4-(aminomethyl)-3-chlorobenzonitrile (60 mg,0.359 mmol) in anhydrous MeOH (1.5 mL) was added TEA (60 mg, 0.594mmol). The solution was stirred at 75° C. for 20 h under N₂. Thereaction mixture was concentrated under reduced pressure to removesolvent. The crude product (150 mg, crude, yellow oil) was directly putinto the next step without further purification. LCMS: RT=1.097 min; MSm/z (ESI) [M+H]⁺=523.4.

Step 3

To a solution of the crude (150.0 mg, 0.287 mmol) in ethyl acetate (1.5mL) was added a solution of 4N HCl/EtOAc (0.4 mL, 1.435 mmol). Thesolution was stirred at room temperature for 1.5 h. The reaction mixturewas concentrated under reduced pressure to remove the solvent. The crudeproduct was purified by prep-HPLC to afford Example 5 (25.4 mg, 21%yield) as a white solid. LCMS: RT=2.217 min; MS m/z (ESI) [M+H]⁺=423.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.41 (s, 1H), 8.41-8.23 (m,2H), 8.07-8.06 (m, 1H), 7.81-7.79 (m, 1H), 7.51-7.49 (m, 2H), 4.63-4.62(m, 2H), 3.75-3.72 (m, 4H), 2.83-2.80 (m, 4H).

General procedure F: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-methoxypropanamido)-1,7-naphthyridine-6-carboxamide

To a solution of Intermediate B (80 mg, 0.24 mmol) in NMP (2 mL) wereadded 3-methoxypropanamide (48.56 mg, 0.47 mmol), Xantphos (27.25 mg,0.05 mmol), Pd₂(dba)₃ (21.56 mg, 0.02 mmol), and K₃PO₄ (149.95 mg, 0.71mmol), and the reaction was stirred at 150° C. for 1 h in a microwavereactor under N₂. The reaction mixture was poured into saturated NaCl(100 mL), and extracted with EA (40 mL×3). The organic layer was driedover Na₂SO₄, filtered and the organic layer was separated, andconcentrated in vacuo. The residue was purified using prep-HPLC elutingwith MeCN in water (0.1% FA) to afford the title compound (36.81 mg,39%). LCMS: 407.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.55 (s, 1H),11.13 (s, 1H), 9.87 (s, 1H), 8.78 (s, 1H), 8.64-8.60 (m, 3H), 8.01 (d,J=1.3 Hz, 2H), 4.68 (d, J=6.3 Hz, 2H), 3.66 (t, J=6.1 Hz, 2H), 3.26 (s,3H), 2.75 (t, J=6.1 Hz, 2H).

Example 6: Synthesis of(R)—N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution of Intermediate A (100 mg, 0.42 mmol) and(R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (126 mg, 0.63 mmol) inanhydrous DMSO (30 mL) was added TEA (106 mg, 1.06 mmol). The solutionwas stirred at 100° C. for 16 h. The reaction mixture was poured intoH₂O (30 mL), and extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash silica gel chromatography. Methyl(R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate(110 mg, 65% yield) was obtained as a yellow solid. LCMS: RT=1.179 min;MS m/z (ESI) [M+H]⁺=404.3.

To a solution of methyl(R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate(100 mg, 0.25 mmol) and 4-(aminomethyl)-3-chlorobenzonitrile (50.0 mg,0.30 mmol) in anhydrous MeOH (1.5 mL) was added TEA (50 mg, 0.50 mmol).The solution was stirred at 75° C. for 20 h under N₂. The reactionmixture was concentrated under reduced pressure to remove solvent. Thecrude product (140 mg, yellow oil) was directly put into the next stepwithout further purification. LCMS: RT=1.099 min; MS m/z (ESI)[M+H]⁺=538.4.

To a solution of(R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide(140 mg, 0.26 mmol) in ethyl acetate (1.5 mL) was added a solution of 4NHCl in ethyl acetate (0.35 mL, 1.30 mmol). The solution was stirred atroom temperature for 1.5 h. The reaction mixture was concentrated underreduced pressure to remove solvent. The crude product was purified byprep-HPLC to afford Example 6 (13.3 mg, 12% yield) as a white solid.LCMS: RT=2.472 min; MS m/z (ESI) [M+H]⁺=424.2. ¹H NMR (400 MHz, CDCl₃) δ12.66 (s, 1H), 8.47 (s, 1H), 8.46-8.31 (m, 2H), 7.70-7.69 (m, 1H),7.58-7.56 (m, 2H), 6.99 (s, 1H), 4.80-4.70 (m, 3H), 3.74 (s, 4H),2.21-2.18 (m, 2H).

Example 22: The synthesis ofN-((6-carbamoylpyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide

To a solution ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide(120 mg, 0.31 mmol) in anhydrous MeOH (2 mL) was added 3M NaOH solution(3 mL). The mixture was stirred at room temperature for 12 h under N₂.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC afford Example 22 (8.5 mg, 7% yield)as a white solid. LCMS: RT=0.890 min; MS m/z (ESI) [M+H]⁺=409.3. ¹H NMR(400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 9.74 (s, 1H), 8.59 (d, J=1.6 Hz,1H), 8.38 (s, 1H), 8.25 (d, J=9.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.89 (dd, J=8.1, 2.0 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J=10.0 Hz,1H), 4.57 (d, J=6.3 Hz, 2H), 3.70 (d, J=5.5 Hz, 8H).

Example 24: The synthesis of5-((5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamido)methyl)picolinicacid

To a solution ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide(120 mg, 0.3 mmol) in anhydrous MeOH (2 mL) was added 3M aqueous NaOH (3ml). The solution was stirred at 70° C. for 20 h under N₂. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-HPLC to afford Example 24 (37 mg, 30% yield) as ayellow solid. LCMS: RT=1.962 min; MS m/z (ESI) [M+H]⁺=410.4; ¹H NMR (400MHz, DMSO-d₆) δ 13.45 (s, 1H), 9.73 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H),8.25 (d, J=9.4 Hz, 1H), 7.93 (dd, J=38.0, 7.9 Hz, 2H), 7.44 (d, J=9.4Hz, 1H), 4.58 (s, 2H), 3.70 (d, J=6.7 Hz, 8H).

Example 41: The synthesis of(S)—N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(piperazine-1-carbonyl)pyrrolidin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution of Intermediate B (150 mg, 0.44 mmol) in DMSO (2 mL) wereadded TEA (0.245 mL, 1.77 mmol), methyl (3S)-pyrrolidine-3-carboxylatehydrochloride (95 mg, 0.57 mmol), and the reaction was stirred at 100°C. for 3 h. The reaction was purified prep-HPLC to afford methyl(S)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylate(120 mg, 0.28 mmol, 63% yield) as a white solid. LCMS: RT=1.102 min; MSm/z (ESI) [M+H]⁺=433.3.

To a solution of methyl(5)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylate(100 mg, 0.23 mmol) in THE (0.5 mL) were added TFA (2 mL), and thereaction was stirred at room temperature for 48 h. The reaction wasdiluted with water (10 mL) and extracted with DCM (10 mL×3). The organiclayer was separated, washed with saturated NaCl solution, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with methanol (0-10%) in chloroform(0-10%) to afford(5)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylicacid (85 mg, 0.20 mmol, 88% yield) as a white solid. LCMS: RT=0.912 min;MS m/z (ESI) [M+H]⁺=419.1.

To a solution of(5)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylicacid (80 mg, 0.19 mmol) in DMF (2 mL) were added tert-butylpiperazine-1-carboxylate (46 mg, 0.25 mmol), HATU (109 mg, 0.29 mmol),TEA (0.080 mL, 0.57 mmol), and the reaction was stirred at roomtemperature for 3 h. The mixture was added H₂O (15 mL) and extractedwith tert-butyl methyl ether (10 mL×3). The organic phase was washedwith brine (10 mL), dried over anhydrous Na₂SO₄, concentrated in vacuumto give tert-butyl(5)-4-(1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carbonyl)piperazine-1-carboxylate(80 mg, 0.14 mmol, 71% yield) as a white solid. LCMS: RT=1.009 min; MSm/z (ESI) [M+H]⁺=587.2.

To a solution of tert-butyl(5)-4-(1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carbonyl)piperazine-1-carboxylate(75 mg, 0.13 mmol) in FA (4 mL), the reaction was stirred at roomtemperature for 2 h. The reaction was concentrated in vacuo. The residuewas purified by pre-HPLC to afford Example 41 (6.86 mg, 0.01 mmol, 11%yield) as a white solid. LCMS: RT=1.296 min; MS m/z (ESI) [M+H]⁺=487.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.42 (s, 1H), 8.26 (d, J=9.1Hz, 2H), 8.00 (d, J=1.2 Hz, 2H), 7.14 (d, J=9.3 Hz, 1H), 4.63 (s, 2H),3.85-3.54 (m, 9H), 2.82-2.80 (m, 2H), 2.75-2.73 (m, 2H), 2.20-2.15 (m,2H).

Example 45: The synthesis of(R)—N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution of Intermediate B (200 mg, 0.59 mmol) in DMSO (2 mL) wereadded TEA (0.41 mL, 2.95 mmol) and tert-butyl(2R)-2-(hydroxymethyl)piperazine-1-carboxylate (191.41 mg, 0.89 mmol),and the reaction was stirred at 100° C. for 2 h under N₂. The reactionwas cooled and poured into water H₂O (200 mL). The mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(30 mL×3), dried over Na₂SO₄, and concentrated. The crude was purifiedby silica gel chromatograph (0˜50% Ethyl acetate in Petroleum) to affordtert-butyl(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate(206 mg, 0.40 mmol, 67% yield) as off-white solid. LCMS: RT=0.888 min;MS m/z (ESI) [M+H]⁺=520.0.

To a solution of tert-butyl(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate(50 mg, 0.10 mmol) in DCM (0.5 mL) were added TFA (0.5 mL, 6.73 mmol),and the reaction was stirred at room temperature for 1 h. The reactionconcentrated in vacuo and dried to afford(R)—N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(50 mg, 0.09 mmol, 94% yield) as yellow oil. LCMS: RT=0.695 min; MS m/z(ESI) [M+H]⁺=420.0.

To a solution of(R)—N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(40 mg, 0.1 mmol) in DCE (5 mL) were added sodium bis(acetyloxy)boranylacetate (80.5 mg, 0.4 mmol) and formaldehyde (4.3 mg, 0.1 mmol), and thereaction was stirred at room temperature for 16 h. The reaction wasconcentrated in vacuo and purified by pre-HPLC to afford Example 45(5.37 mg, 0.012 mmol, 13% yield) as a red solid. LCMS: RT=0.870 min; MSm/z (ESI) [M+H]⁺=434.0. ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H),9.78-9.76 (m, 1H), 8.76 (s, 1H), 8.43 (s, 1H), 8.28 (d, J=9.2 Hz, 1H),8.14 (s, 1H), 8.00 (s, 2H), 7.48 (d, J=9.5 Hz, 1H), 4.85-4.84 (m, 1H),4.65-4.63 (m, 2H), 4.59-4.24 (m, 4H), 3.72-3.70 (m, 3H), 3.00-2.92 (m,3H), 2.35 (s, 3H).

Example 46: The synthesis of(R)-2-(4-acetyl-3-(hydroxymethyl)piperazin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

To a solution of(R)—N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(20 mg, 0.05 mmol) in DCM (1 mL) were added TEA (0.066 mL, 0.48 mmol)and acetyl chloride (0.003 mL, 0.04 mmol), and the reaction was stirredat room temperature for 3 h. The reaction was concentrated in vacuo andpurified by pre-HPLC to afford Example 46 (6.60 mg, 0.014 mmol, 30%yield) as a white solid. LCMS: RT=0.964 min; MS m/z (ESI) [M+H]⁺=462.0.¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 9.85-9.82 (m, 1H), 8.76 (s,1H), 8.41 (s, 1H), 8.29 (d, J=9.5 Hz, 1H), 8.01-7.99 (m, 2H), 7.47-7.45(m, 1H), 4.95-4.92 (m, 1H), 4.67-4.62 (m, 2H), 4.61-4.22 (m, 4H), 4.07-3.75 (m, 1H), 3.51-3.49 (m, 2H), 3.16-2.82 (m, 2H), 2.08 (d, J=15.3 Hz,3H).

Example 50: The synthesis of methyl(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylate

To a solution of Intermediate B (100 mg, 0.29 mmol) in NMP (2 mL) wereadded 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (107.86mg, 0.44 mmol), TEA (0.12 mL, 0.88 mmol). The sealed vial was irradiatedin a microwave reactor at 140° C. for 2.5 h. The reaction was purifiedusing silica gel column chromatography eluting with water/CH₃CN/HCOOH togive 1-(tert-butyl) 2-methyl(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1,2-dicarboxylate(60 mg, 0.11 mmol, 37% yield) as a white solid. LCMS: RT=1.871 min; MSm/z (ESI) [M+H]⁺=548.2.

A solution of 1-(tert-butyl) 2-methyl(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1,2-dicarboxylate(55 mg, 0.10 mmol) in formic acid (2 mL) was stirred at room temperaturefor 2 h. The reaction was purified by pre-HPLC to afford Example 50(15.66 mg, 0.03 mmol, 35% yield) as a white solid. LCMS: RT=1.309 min;MS m/z (ESI) [M+H]⁺=448.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.80 (s, 1H),8.76 (s, 1H), 8.42 (s, 1H), 8.27 (d, J=9.4 Hz, 1H), 8.18 (s, 1H), 8.00(d, J=1.2 Hz, 2H), 7.48 (d, J=9.5 Hz, 1H), 4.63 (d, J=6.4 Hz, 2H),4.37-4.34 (m, 1H), 3.95-3.93 (m, 1H), 3.66 (s, 3H), 3.61-3.54 (m, 2H),3.49-3.46 (m, 2H), 3.03-3.01 (m, 1H), 2.75-2.71 (m, 1H).

Example 51: The synthesis of(R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylicacid

To a solution of Intermediate B (100 mg, 0.29 mmol) in NMP (2 mL) wereadded 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (107.86mg, 0.44 mmol), TEA (0.123 mL, 0.88 mmol). The sealed vial wasirradiated in a microwave reactor at 140° C. for 2.5 h. The reaction waspurified using silica gel column chromatography eluting withwater/CH₃CN/HCOOH to give(R)-1-(tert-butoxycarbonyl)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylicacid (50 mg, 0.09 mmol, 32% yield) as a white solid. LCMS: RT=1.094 min;MS m/z (ESI) [M+H]⁺=534.1.

To a solution of(R)-1-(tert-butoxycarbonyl)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylicacid (45 mg, 0.08 mmol) in formic acid (2 mL), the reaction was stirredat room temperature for 2 h. The reaction was purified by pre-HPLC togive Example 51 (11.18 mg, 0.03 mmol, 31% yield) as a white solid. LCMS:RT=1.249 min; MS m/z (ESI) [M+H]⁺=434.2. ¹H NMR (400 MHz, DMSO-d₆) δ13.35 (s, 1H), 9.83 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 8.32 (d, J=9.3Hz, 1H), 8.01 (s, 2H), 7.51 (d, J=9.3 Hz, 1H), 4.75-4.73 (m, 1H), 4.63(d, J=6.1 Hz, 2H), 4.37-4.34 (m, 1H), 3.44-2.99 (m, 6H).

Example 60: The synthesis of(R)—N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution of2-chloro-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide(250 mg, 0.67 mmol) in DMSO (5 mL) were added TEA (0.279 mL, 2.01 mmol),tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (23 mg, 0.20mmol), and the reaction was stirred at 100° C. for 2 h under N₂. Thereaction was diluted with water (200 mL), extracted with EtOAc (50mL×3). The combined organic layer was separated, washed with furthersaturated NaCl solution (100 mL×3), and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting withmethanol (0˜15%) in chloroform. The organic layers were collected,concentrated in vacuo, and dried to afford the title compound tert-butyl(R)-4-(6-((2-chloro-4-cyanobenzyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate(50 mg, 0.12 mmol, 50% yield) as a white solid. LCMS: RT=1.471 min; MSm/z (ESI) [M+H]⁺=553.3.

To a solution of(R)-4-(6-((2-chloro-4-cyanobenzyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate(270 mg, 0.49 mmol) was added TFA (2 mL, 26.93 mmol), and the reactionwas stirred at room temperature for 1 h. The reaction mixture was pouredinto saturated Na₂CO₃ (100 mL), and extracted with EtOAc (40 mL×3), theorganic layer was dried over Na₂SO₄, filtered, and evaporated to affordExample 60 (200 mg, 0.44 mmol, 90% yield) as a yellow oil. LCMS:RT=0.740 min; MS m/z (ESI) [M+H]⁺=453.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.78 (s, 1H), 8.82 (s, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.34 (s, 1H), 8.14(s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 5.08-5.06 (m,1H), 4.66-4.52 (m, 4H), 3.59-3.51 (m, 2H), 3.21-3.18 (m, 2H), 2.98-2.88(m, 4H).

Example 59: The synthesis of(R)—N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution of(R)—N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(50 mg, 0.11 mmol) in DCM (1 mL) were added sodium bis(acetyloxy)boranylacetate (69.86 mg, 0.33 mmol), formaldehyde (18.42 mg, 0.22 mmol), andthe reaction was stirred at room temperature for 1 h. The reaction wasdiluted with EtOAc (30 mL) and water (50 mL). The organic layer wasseparated, and concentrated in vacuo. The residue was purified usingprep-HPLC to afford Example 59 (13.39 mg, 0.03 mmol, 26% yield) as apale yellow solid. LCMS: RT=1.376 min; MS m/z (ESI) [M+H]⁺=467.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.42 (s, 1H), 8.28 (d, J=9.4 Hz, 1H),8.21 (s, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.81 (dd, J=8.0, 1.4 Hz, 1H), 7.52(d, J=8.1 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 4.64 (d, J=6.1 Hz, 2H),4.55-4.44 (m, 1H), 4.37-4.35 (m, 1H), 3.72-3.70 (m, 2H), 3.42-3.40 (m,1H), 3.21-3.13 (m, 1H), 2.98-2.83 (m, 2H), 2.28 (s, 3H), 2.24-2.20 (m,1H), 2.11-2.04 (m, 1H).

Example 63: The synthesis of(R)-2-(4-acetyl-3-(hydroxymethyl)piperazin-1-yl)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

To a solution of(R)—N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(70 mg, 0.15 mmol) in DCM (3 mL) were added acetyl chloride (0.105 mL,0.10 mmol), and the reaction was stirred at room temperature for 1 h.The reaction was diluted with EtOAc (30 mL) and water (50 mL). Theorganic layer was separated, and concentrated in vacuo. The residue waspurified using prep-HPLC to afford Example 63 (6.75 mg, 0.01 mmol, 9%yield) as a pale yellow solid. LCMS: RT=1.620 min; MS m/z (ESI)[M+H]⁺=495.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.40-8.38 (m,1H), 8.30 (d, J=8.9 Hz, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.81 (d, J=8.3Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.44 (m, 1H), 4.86-4.84 (m, 1H),4.65-4.63 (m, 2H), 4.55-4.47 (m, 2H), 4.35-4.33 (m, 2H), 4.07-4.05 (m,1H), 3.30-3.78 (m, 1H), 3.50 (d, J=7.1 Hz, 2H), 3.00-2.96 (m, 1H), 2.09(d, J=14.9 Hz, 3H).

Example 72: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(4-(3-hydroxypropanoyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(50 mg, 0.13 mmol) in DCM (4 mL) were added 3-hydroxypropanoic acid(0.011 mL, 0.13 mmol), HATU (73.23 mg, 0.19 mmol), and DIEA (0.064 mL,0.39 mmol), and the reaction was stirred at room temperature for 16 h.The reaction mixture was poured into saturated NaCl (100 mL), andextracted with ethyl acetate (40 mL×3). The combined organic layers weredried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby prep-HPLC to afford Example 72 (7.07 mg, 0.02 mmol, 12% yield) as apale yellow solid. LCMS: RT=1.420 min; MS m/z (ESI) [M+H]⁺=462.1. ¹H NMR(400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 9.77 (t, J=6.1 Hz, 1H), 8.76 (s,1H), 8.45 (s, 1H), 8.29 (d, J=9.4 Hz, 1H), 8.00 (s, 2H), 7.50 (d, J=9.5Hz, 1H), 4.63 (d, J=6.2 Hz, 2H), 4.55 (d, J=5.3 Hz, 1H), 3.84-3.81 (m,4H), 3.69-3.66 (m, 6H), 2.57-2.55 (m, 2H).

Example 73: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(4-(3-methoxypropanoyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

To a solution ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide(50 mg, 0.13 mmol) in DCM (4 mL) were added 3-hydroxypropanoic acid(0.011 mL, 0.13 mmol), HATU (73.23 mg, 0.19 mmol), and DIEA (0.064 mL,0.39 mmol), and the reaction was stirred at room temperature for 16 h.The reaction mixture was poured into saturated NaCl (100 mL), andextracted with ethyl acetate (40 mL×3). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified using prep-HPLC to afford Example 73 (6.18 mg, 0.01 mmol, 6%yield) as a white solid. LCMS: RT=1.505 min; MS m/z (ESI) [M+H]⁺=476.2.¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 9.77 (t, J=6.3 Hz, 1H), 8.76(s, 1H), 8.45 (s, 1H), 8.29 (d, J=9.4 Hz, 1H), 8.00 (d, J=1.2 Hz, 2H),7.50 (d, J=9.5 Hz, 1H), 4.63 (d, J=6.3 Hz, 2H), 3.83-3.81 (m, 4H),3.65-3.56 (m, 6H), 3.24 (s, 3H), 2.64 (t, J=6.6 Hz, 2H).

Example 85: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(2-oxomorpholino)-1,7-naphthyridine-6-carboxamide

To a solution of Intermediate B (150 mg, 0.44 mmol) in DMSO (5 mL) wereadded ethyl (2-hydroxyethyl)glycinate (195 mg, 1.32 mmol) and TEA (222mg, 2.2 mmol), and the reaction was stirred at 100° C. for 16 h. Themixture concentrated and purified by pre-TLC to afford example 85 (19.20mg, 11%).

Example 85: LCMS: 405.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s,1H), 9.79 (s, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 8.36 (d, J=9.3 Hz, 1H),8.00 (d, J=1.4 Hz, 2H), 7.39 (d, J=9.4 Hz, 1H), 4.70-4.54 (m, 6H),4.00-3.88 (m, 2H).

Example 124: The synthesis of2-(4-aminopiperidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

To a solution of example 123 (100 mg, 0.198 mmol) was added formic acid(3 mL, 0.225 mmol), and the reaction was stirred at 25° C. for 3 h. Thereaction was concentrated in vacuo. The residue was purified byprep-HPLC to afford example 124 (34.39 mg, 43%). LCMS: 404.3 [M+H]⁺; NMR(400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.76 (s, 1H), 8.38 (s, 1H), 8.35 (s,1H), 8.25 (s, 1H), 8.01-7.97 (m, 2H), 7.47 (d, J=9.5 Hz, 1H), 4.63 (d,J=5.4 Hz, 2H), 4.57 (d, J=13.5 Hz, 2H), 3.25-3.17 (m, 1H), 3.10 (t,J=11.9 Hz, 2H), 1.96 (d, J=12.5 Hz, 2H), 1.45-1.42 (m, 2H).

Example 126: The synthesis of(S)-2-(3-aminopyrrolidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

To a solution of example 125 (110 mg, 0.225 mmol) was added formic acid(3 mL, 0.225 mmol), and the reaction was stirred at 25° C. for 3 h. Thereaction was concentrated in vacuo. The residue was purified byprep-HPLC to afford example 126 (22.01 mg, 24%). LCMS: 390.5 [M+H]⁺; NMR(400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=18.9 Hz,2H), 8.25 (d, J=9.2 Hz, 1H), 8.00 (s, 2H), 7.08 (d, J=9.1 Hz, 1H), 4.64(d, J=4.8 Hz, 2H), 3.81-3.69 (m, 4H), 3.65-3.62 (m, 1H), 2.23-2.21 (m,1H), 1.99-1.97 (m, 1H).

Example 15: The synthesis of (6-cyanopyridin-3-yl)methyl(R)-5-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1,7-naphthyridine-6-carboxylate

To a solution of 5-(bromomethyl)picolinonitrile (100 mg, 0.51 mmol) inDMF (3 mL) were added carboxylic acid (155.23 mg, 0.56 mmol, which wasobtained via a similar procedure as example 3), NaHCO₃ (94.74 mg, 1.13mmol), and the reaction was stirred at room temperature for 16 h. Thereaction was diluted with H₂O (30 mL), extracted with EA (30 mL×3). Thecombined organic layers were washed with aq. NaCl (30 mL×3), dried andconcentrated in vacuo. The residue was purified by prep-HPL to affordexample 15 (4.1 mg, 2%). LCMS: 392.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.90 (s, 1H), 8.32-8.08 (m, 5H), 7.14-6.91 (m, 1H), 5.52-5.50 (m, 2H),5.03-5.01 (m, 1H), 4.45-4.43 (m, 1H), 3.63-3.61 (m, 4H), 2.03- 2.01 (m,3H).

Example 102: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(2-oxopiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

A solution of example 101 (150 mg, 0.298 mmol) in HCl/EA (3M, 2 mL) wasstirred at room temperature for 1 h. The mixture was filtered andconcentrated. The crude was purified by pre-HPLC to give example 102(24.15 mg, 19%). LCMS: 404.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.61(s, 1H), 10.00 (s, 1H), 9.65 (s, 2H), 8.80 (d, J=15.4 Hz, 2H), 8.70 (d,J=9.3 Hz, 1H), 8.36 (d, J=9.2 Hz, 1H), 8.02 (d, J=1.4 Hz, 2H), 4.68 (d,J=6.2 Hz, 2H), 4.43-4.23 (m, 2H), 4.05 (s, 2H), 3.67-3.50 (m, 2H).

Example 128:2-(3-aminoazetidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

A mixture of example 127 (28 mg, 0.059 mmol) in HCl/EA (3 M, 5 mL) wasstirred at rt for 1 h, and the reaction was concentrated in vacuo. Theresidue was purified by pre-HPLC to afford example 128 (29.91 mg, 38%).LCMS: 376 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.76 (s,1H), 8.41 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.00 (s, 2H), 6.92 (d, J=9.1Hz, 1H), 4.63 (d, J=6.4 Hz, 2H), 4.33 (t, J=8.1 Hz, 2H), 3.93-3.85 (m,1H), 3.82-3.73 (m, 2H).

Example 134: The synthesis of tert-butyl4-(6-(((5-cyanopyrazin-2-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(6-(((5-chloropyrazin-2-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate(150 mg, 0.300 mmol, which was obtained via General Procedure D) in DMF(2 mL) were added Zn(CN)₂ (35.23 mg, 0.300 mmol), Pd(dppf)Cl₂ (43.91 mg,0.060 mmol), and the reaction was stirred at 130° C. for 16 h under N₂.The reaction was poured into water (50 mL), extracted with EA (30 mL×3).The organic layer was washed with aq. NaCl (30 mL×3), dried over Na₂SO₄,and concentrated. The crude was purified by pre-HPLC to afford example134 (8.28 mg, 5%). LCMS: 491.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.29(s, 1H), 9.66-9.65 (m, 1H), 9.18 (d, J=1.2 Hz, 1H), 8.88 (s, 1H), 8.46(s, 1H), 8.30 (d, J=9.4 Hz, 1H), 7.49 (d, J=9.4 Hz, 1H), 4.81 (d, J=6.0Hz, 2H), 3.83-3.81 (m, 4H), 3.49-3.46 (m, 4H), 1.44 (s, 9H).

Example 163: The synthesis ofN-((6-cyanopyridin-3-yl)methyl)-5-methoxy-2-morpholino-1,7-naphthyridine-6-carboxamide

To a solution of example 10 (100 mg, 0.256 mmol) in acetone (2 mL) wasadded MeI (360 mg, 2.536 mmol) and K₂CO₃ (180 mg, 1.302 mmol), and thereaction was heated to 50° C. for 2 h, and the solution was diluted withwater (10 mL) and extracted with EA (5 mL×3), the EA layer was combinedand washed with brine (5 mL), and dried over Na₂SO₄, and concentrated,and the residue was purified by pre-HPLC to afford example 163 (3.76 mg,4%). LCMS: 405 [M+H]⁺; NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.76 (s,1H), 8.35 (d, J=9.4 Hz, 1H), 8.13 (s, 1H), 8.01 (s, 2H), 7.42 (d, J=9.3Hz, 1H), 4.64 (d, J=5.9 Hz, 2H), 4.47 (s, 3H), 3.75-3.72 (m, 8H).

Example 40: The synthesis of5-hydroxy-N-((6-hydroxypyridin-3-yl)methyl)-2-morpholino-1,7-naphthyridine-6-carboxamide

To a solution of example 34 (129 mg, 0.33 mmol) in acetonitrile (5.0 mL)was added iodotrimethylsilane (0.14 mL, 1.00 mmol). The resultingmixture was stirred at 80° C. for 18 h. The residue was purified byprep-HPLC to give example 40 (50.95 mg, 41%). LCMS: 382.0 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 13.60 (s, 1H), 11.48 (s, 1H), 9.47 (t, J=6.1 Hz,1H), 8.41 (s, 1H), 8.28 (d, J=9.4 Hz, 1H), 7.51 (dd, J=9.5, 2.6 Hz, 1H),7.48 (d, J=9.5 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 6.32 (d, J=9.4 Hz, 1H),4.24 (d, J=6.3 Hz, 2H), 3.75 (s, 4H), 3.73 (s, 4H).

The following compounds were made according to the general procedure asshown in the table 2 below:

TABLE 2 Ex. General procedure 3 C 4 C 5 D 6 D 7 D 9 D 10 D 16 A 17 D 18D 19 A 20 D 21 C 22 Hydrolyze of example 10 23 C 24 Hydrolyze of example10 26 A 27 D 28 deBoc of example 29 29 A 31 C 32 C 33 C 34 D 35 D 36 D37 D 38 A 39 D Followed by de-Boc 40 Demethylation of example 34 41 A 42A 45 A Followed by -Boc and +Me 46 A Followed by -Boc and +Ac 47 A 48 D50 A Followed by de-Boc 51 A Followed by de-Boc 57 D 59 methylation ofexample 60 60 A Followed by deBoc 63 Acetylation of example 60 64 A 66 A70 A 71 A 72 Example 28, then amide cross coupling 73 Example 28, thenamide cross coupling 74 A 75 A 84 A 85 A 86 A 89 A 92 A 94 A 95 A 96 A100 F 101 F 102 De-Boc of example 101 103 F 119 A 120 A 121 A 123 A 124deBoc of example 123 125 A 126 deBoc of example 125 127 128 De-Boc ofexample 127 132 A 133 A 134 Cyanation of a pdt from General Procedure D135 A 136 C 137 A 138 A 139 A 140 A 142 A 143 F 144 F 149 A 150 A 151 A152 A 153 A 154 A 155 A 156 A 157 A 158 A 160 C 163 Methylation ofexample 10

BIOLOGICAL EXAMPLES Example A: PHD2 Enzymatic Assay Procedure

Compound DMSO stock preparation: All compounds were reconstituted into20 mM stock by DMSO.

Compound storage: All compounds in DMSO were stored at RT in adesiccator for short-term storage (up to 3 months). Leftover compoundswere store at−20 for longer term.

Working Stock Preparation:

-   -   Reference Roxadustat (FG-4592) was 3-fold serial diluted from        400 μM for 10 doses in DMSO.    -   The compounds were 3-fold serial diluted from 400 μM for 10        doses in DMSO.    -   Prepared 200×positive control (400 μM, FG-4592) and 200×vehicle        control (100% DMSO).    -   Centrifuged compound plates at 1000 rpm for Imin.

Compound Screening:

-   -   a) Transferred 40 nl compound dilutions into each well of assay        plates using Echo 655;    -   b) Sealed the assay plate and centrifuge compound plates at 1000        rpm for Imin.    -   c) Prepared and add 4 μL of the 2×PHD2 enzyme working solution        to individual well of the assay plate.    -   d) Sealed the assay plate and centrifuge compound plates at 1000        rpm for Imin. Incubate plate at RT for 30 min.    -   e) Prepared and add 4 μl 2×PHD2 substrate working solution to        each well of the assay plate.    -   f) Prepared and added 4 μL 4×stop solution to the each well of        the assay plate.    -   g) Prepared 4×detection solution with AlphaScreen Streptavidin        Donor beads, AlphaScreen Protein A Acceptor beads and        Hydroxy-HIF-1α (Pro564) (D43B5) XP® Rabbit mAb.    -   h) Added 4 μL 4×detection solution to the each well of the assay        plate. repeat at step d.    -   i) Read Alphascreen signal on Envision HTS plate reader.

Data Analysis

ALPHASCREEN signal (ALPcmpd) is calculated for each well2.2% Inhibition is calculated as follow:

${\%{Inhibition}} = {\left\lbrack {1 - \frac{{\overset{\_}{ALP}}_{compound} - {\overset{\_}{ALP}}_{positive}}{{\overset{\_}{ALP}}_{vehicle} - {\overset{\_}{ALP}}_{positive}}} \right\rbrack \times 100}$

ALP _(positive): The average ALP for the positive controls across theplate.ALP _(vehicle): The average ALP for the negative controls across theplate.

2.3 Calculate IC₅₀ and Plot effect-dose curve of compounds:

Calculated IC₅₀ by fitting % inhibition values and log of compoundconcentrations to nonlinear regression (dose response−variable slope)with Graphpad 8.0.

Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((LogIC50−X)*HillSlope))

X: log of Inhibitor concentration; Y: % Inhibition.

Example C: Caco-2 HIF1α-HiBiT Assay

Cells: Caco2-HIF1α-HiBiT-clone-1 cells.

Culture medium: EMEM contain 20% FBS, 1% Penicillin-Streptomycin forCaco-2

Cell Passage Procedure

-   -   Cleaned working surface of bio-safety cabinet with 75% ethanol,        allow approximately 5 minutes to elapse before using cabinet.    -   Aspirated cell culture medium and rinse the cell layer gently        with 5 ml DPBS for twice. Then remove DPBS.    -   Added 2 ml 0.25% trypsin to the flask and place it at a 37° C.,        5% CO₂ incubator for 2 minutes.    -   After 2 minutes tripsinization, quenched trypsin with 10 ml cell        culture medium.    -   Gently pipetted the cells up and down to dissociate cell clumps,        transferred cell suspension into the 15 ml tube.    -   Verified cell density using the cell counter.    -   Diluted cell suspension with culture medium and transfer 2.0*106        cells to a T75 flask.    -   Maintained cells at the 37° C., 5% CO₂ incubator under certain        humidity for 3 days.

Plating Cells (Day 1)

-   -   Prepared plating medium.    -   Aspirated cell culture medium. Wash cells gently with 10 ml PBS        and remove PBS. Dissociated cells with 3 ml 0.25% trypsin and        terminate digestion with 10 ml cell culture medium.    -   Determined cell density with the cell counter.    -   Plated Caco-2-HIF1α-HiBiT-clone-1 cells in a 384-well plate        (Corning-3765) at the density of 5.5 k cells per well within 20        μl medium Maintain cells in the incubator overnight.

Compound Treatment (Day 3)

-   -   Dissolved the compound stock solution in DMSO and conduct serial        dilution with cell culture medium to achieve the working        concentration.    -   Added 20 μL of media containing desired concentration of        distinct compound into per well to achieve the final compound        concentration.    -   Incubated cells at the 37° C., 5% CO₂ incubator for 6 h.

Detection (Day 3)

-   -   Prepared 2×detect solution: Dilute LgBiT Protein and Nano-Glo®        HiBiT Lytic Substrate 1:2:100 into an appropriate volume of room        temperature Nano-Glo® HiBiT Lytic Buffer in a new tube.    -   Prepared 1×detect solution: Add equal volume PBS into 2×detect        solution to prepare 1×detect solution.    -   Washed cells with PBS and add 30 ul 1×solution into well and        mix.    -   Waited at least 10 minutes for equilibration of LgBiT and HiBiT        in the lysate. Measured luminescence using Envision.

The data from examples A and C are shown in Table 3.

TABLE 3 Ex. PHD2 Caco2-HIF1α-HiBit assay - EC50 3 B A 4 B E 5 B D 6 B B7 B B 9 A B 10 A A 15 E E 16 A E 17 E E 18 B C 19 B E 20 A B 21 C E 22 EE 23 A C 24 E E 26 A B 27 A A 28 A E 29 A A 31 E 32 A E 33 C 34 C D 35 CE 36 D E 37 A D 38 A B 39 A E 40 D E 41 A E 42 A B 45 A E 46 A E 47 A A48 E E 50 A E 51 A E 57 A D 59 A B 60 B E 63 B D 64 D E 66 A E 70 B B 71B B 72 A C 73 A C 74 A B 75 A C 84 A C 85 A E 86 A E 89 A B 92 A C 94 AD 95 A E 96 A E 100 B D 101 A B 102 D 103 A B 119 A E 120 A E 121 A D123 A B 124 A E 125 A A 126 A E 127 A A 128 C C 132 A C 133 B B 134 E135 A 137 A A 138 A B 139 A B 140 B B 142 B B 143 A A 144 B B 149 A B150 A A 151 B 152 A B 153 B 154 A 155 D 163 D PHD2 (nM): 0 < A ≤ 5; 5 <B ≤ 20; 20 < C ≤ 100; 100 < D ≤ 1,000; 1,000 < E < 100,000Caco2-HIF1α-HiBit assay (EC50, nM): 0 < A ≤ 2,500; 2,500 < B ≤ 5,000;5,000 < C ≤ 7500; 7,500 < D ≤ 10,000; 10,000 < E ≤ 100,000

What is claimed is:
 1. A compound of Formula (I), or a pharmaceuticallyacceptable salt or stereoisomer thereof:

wherein: R¹ is

each of which optionally substituted with one or more R^(1a); eachR^(1a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—NR^(b)C(═O)R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R^(1a) on thesame atom are taken together to form an oxo;

Y is —NR⁶—; R⁶ is hydrogen; L is —(CR⁷R⁸)_(p); each R⁷ and R⁸ arehydrogen; p is 1; Ring A is aryl or heteroaryl; each R⁹ is independentlyhalogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; n is 1 or 2; each R^(a) isindependently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; each R^(c) andR^(d) are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; or R^(c) andR^(d) are taken together with the atom to which they are attached toform a heterocycloalkyl optionally substituted with one or more R; andeach R is independently halogen, —CN, —OH, —OC₁-C₆alkyl,—S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂, —S(═O)₂NHC₁-C₆alkyl,—S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl, —N(C₁- C₆alkyl)₂,—NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —C(═O)OH, —C(═O)OC₁-C₆alkyl,—C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂, —C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;or two R on the same atom are taken together to form an oxo.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ring A is phenyl.
 3. The compound of claim1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein Ring A is 6-membered heteroaryl.
 4. The compound of claim 1, ora pharmaceutically acceptable salt or stereoisomer thereof, wherein nis
 1. 5. The compound of claim 1, or a pharmaceutically acceptable saltor stereoisomer thereof, wherein each R⁹ is independently halogen or—CN.
 6. The compound of claim 1, or a pharmaceutically acceptable saltor stereoisomer thereof, wherein R¹ is

optionally substituted with one or more R^(1a).
 7. The compound of claim1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein each R^(1a) is independently halogen, —OH, —OR^(a),—NR^(b)C(═O)R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆heteroalkyl, orcycloalkyl; or two R^(1a) on the same atom are taken together to form anoxo.
 8. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 9. Thecompound of claim 1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 15. A method of treatinga disease or disorder in a subject, the method comprising administeringto the subject a compound of claim 1, or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein the disease or disorder isinflammatory bowel disease (IBD).
 16. The method of claim 15, whereinthe disease or disorder is ulcerative colitis (“UC”) or Crohn's disease(“CD”).
 17. A pharmaceutical composition comprising (i) a compound ofFormula (I), or a pharmaceutically acceptable salt or stereoisomerthereof:

wherein: R¹ is

each of which optionally substituted with one or more R^(1a); eachR^(1a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—NR^(b)C(═O)R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R^(1a) on thesame atom are taken together to form an oxo;

Y is —NR⁶—; R⁶ is hydrogen; L is —(CR⁷R⁸)_(p); each R⁷ and R⁸ arehydrogen; p is 1; Ring A is aryl or heteroaryl; each R⁹ is independentlyhalogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; n is 1 or 2; each R^(a) isindependently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; each R^(c) andR^(d) are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more R; or R^(c) andR^(d) are taken together with the atom to which they are attached toform a heterocycloalkyl optionally substituted with one or more R; andeach R is independently halogen, —CN, —OH, —OC₁-C₆alkyl,—S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂, —S(═O)₂NHC₁-C₆alkyl,—S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl, —N(C₁- C₆alkyl)₂,—NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —C(═O)OH, —C(═O)OC₁-C₆alkyl,—C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂, —C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;or two R on the same atom are taken together to form an oxo; and (ii) apharmaceutically acceptable excipient.
 18. The pharmaceuticalcomposition of claim 17, wherein Ring A is phenyl.
 19. Thepharmaceutical composition of claim 17, wherein Ring A is 6-memberedheteroaryl.
 20. The pharmaceutical composition of claim 17, wherein nis
 1. 21. The pharmaceutical composition of claim 17, wherein each R⁹ isindependently halogen or —CN.
 22. The pharmaceutical composition ofclaim 17, wherein R¹ is

optionally substituted with one or more R^(1a).
 23. The pharmaceuticalcomposition of claim 17, wherein each R^(1a) is independently halogen,—OH, —OR^(a), —NR^(b)C(═O)R^(a), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆heteroalkyl, or cycloalkyl; or two R^(1a) on the same atom aretaken together to form an oxo.
 24. The pharmaceutical composition ofclaim 17, wherein the compound of Formula (I) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 25. Thepharmaceutical composition of claim 17, wherein the compound of Formula(I) is:

or a pharmaceutically acceptable salt thereof.
 26. The pharmaceuticalcomposition of claim 17, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 27. The pharmaceuticalcomposition of claim 17, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 28. The pharmaceuticalcomposition of claim 17, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 29. The pharmaceuticalcomposition of claim 17, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
 30. The pharmaceuticalcomposition of claim 17, wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.